Current ultrasound-guided drug delivery systems mainly use commercial ultrasound contrast agent to carry drugs, for which the ultrasound contrast agent may performance the function of trafficking and ultrasonically-triggered drug releasing. However, the mentioned drug delivery systems might encounter following issues: (1) “Background leakage”, that is, the leakage of drugs from the vehicle during the storage process, or in the in vivo circulation process before reaching and being triggered at target site; and (2) “seeing” the contrast agent at non-affected area in a series of image acquisition, the drug may also be released by the triggering at non-affected area, which makes the mentioned drug delivery method more difficult to control the timing and location of release. Therefore, in addition to medical diagnostic ultrasound, it is necessary to find a new medical imaging technology for vehicle's tracking.
Another known technology relates to the use of MR image-guided focus ultrasound to achieve site-specific drug delivery. It uses magnetic resonance imaging to guide ultrasound equipment for the energy focusing position, so that ultrasound can be projected and focused on a specific location. By the ultrasonic energy, the vascular barrier at a specific location will be opened temporarily or the permeability of tissue will be increased, so that the drug delivered to the area by circulation can successfully penetrate the barrier and get into the affected tissues. However, in that technology, drugs do not be encapsulated in a vehicle, which may be confronted with the problems that (1) drugs will enter the systemic circulation and produce side effects, for anticancer drugs with higher toxicity; and (2) certain drugs having short half-life in blood may be non-effective before reaching the target area.
The third conventional drug delivery involves the use of single crystal iron oxide as the magnetic shell structure to lower the leakage of drugs, and the use of “alternating magnetic field” to generate changes in the volume of shell material (i.e., magnetostriction), resulting in cracked ferric oxide shell and drug release (Adv. Mater. 2008, 20, 2690-2695). However, there are problems in above drug delivery to limit its application: (1) the technology needs an alternating magnetic field of high-intensity to trigger drug delivery, and there is no commercially available medical equipment so far, for that the safety to human body is still unable to verify, and the temperature in tissues is more difficulty to be controlled; (2) it is uncertain whether the magnetic shell used in the technology is superparamagnetic, where the superparamagnetism is an important characteristic of MRI T2 imaging; (3) it is unknown if there are any magnetic resonance imaging (MRI) signal changes of the vehicle could be induced after the triggering in magnetic field, or impossible to examine the state of vehicle by the MRI signal variations; (4) although the method may be combined with “MRI” and “magnetism-controlled drug delivery”, the drug delivery device actually can not be integrated with the magnetic resonance imaging equipment, because the main field for MRI is a static magnetic field, and the intensity of radio frequency electromagnetic field is too low, both of which are unable to produce the required alternating magnetic field to carry out the magnetism-controlled drug release, making diagnosis and treatment of that method hardly be conducted on the platform of MRI device; and (5) generally the “magnetically-triggered drug vehicle” must take magnetic field-triggering for drug release, whereas the use of electromagnetic field as a triggering energy may result in a risk of health, for that electromagnetic field is not easy to precisely focus and directionally spread, and probably is a quite interference to general medical equipment.
Based on the consideration of the disadvantages mentioned above, the inventor invents to combine “magnetic resonance imaging”, “ultrasonically-triggered drug release” and “low background leakage” in a drug vehicle structure that can track the image of drug delivery vehicle by MRI to confirm if adequate amount of which reach to a specific location, and trigger the drug release from delivery vehicle immediately by ultrasound to achieve the precise administration of treatment, and avoid the lower dosage efficiency caused by the patient's movement or the time difference, which may result in different conditions at the time of triggering from which at imagining. Although the combination of MRI and ultrasound had been described in clinical cases of commercial medical device, which cases mainly using MRI-guided ultrasound to focus and conduct burning therapy on tumor, no prior art ever disclosed a drug delivery method by using MRI to track vector images, and the subsequent use of ultrasound to trigger drug release.